Director's cut: The pharmaceutically relevant sulfonamide group is shown to be a competent directing group for [Cp*Rh(OAc)(2)]-catalyzed C-H functionalizations. Reactions of the cyclometalated intermediate with internal alkynes provide access to a wide range of sultam derivatives. The reaction is high yielding and works best under aerobic conditions with catalytic amounts of CuOAc as an oxidation mediator. Cp* = C(5)Me(5).

Macrocyclic compounds are an attractive modality for drug development, but the limited availability of large, structurally diverse macrocyclic libraries hampers the discovery of leads. Here, we describe the discovery of efficient macrocyclization reactions based on thiol-to-amine ligations using bis-electrophiles, their application to synthesize and screen large libraries of macrocyclic compounds, and the identification of potent small macrocyclic ligands. The thiol-to-amine cyclization reactions showed unexpectedly high yields for a wide substrate range, which obviated product purification and enabled the generation and screening of an 8988 macrocycle library with a comparatively small effort. X-ray structure analysis of an identified thrombin inhibitor (Ki = 42 ± 5 nM) revealed a snug fit with the target, validating the strategy of screening large libraries with a high skeletal diversity. The approach provides a route for screening large sub-kilodalton macrocyclic libraries and may be applied to many challenging drug targets.

Larger condensed arenes are of interest owing to their electro- and photochemical properties. An efficient synthesis is the catalyzed aromatic annulation of a smaller arene with two alkyne molecules. Besides difunctionalized starting materials, directed C-H functionalization can be used for such aromatic homologation. However, thus far the requirement of either pre-functionalized substrates or suitable directing groups were limiting this approach. Herein, we describe a rhodium(III)-catalyzed method allowing the use of completely unbiased arenes and internal alkynes. The reaction works best with copper(II) 2-ethylhexanoate and decabromodiphenyl ether as the oxidant combination. This aromatic annulation tolerates a variety of functional groups and delivers homologated condensed arenes. Aside from simple benzenes, naphthalenes and higher condensed arenes provide access to highly substituted and highly soluble acenes structures having important electronic and photophysical properties.

Chiral spirocyclic sultams are a valuable compound class in organic and medicinal chemistry. A rapid entry to this structural motif involves a [3+2] annulation of an N-sulfonyl ketimine and an alkyne. Although the directing-group properties of the imino group for C-H activation have been exploited, the developments of related asymmetric variants have remained very challenging. The use of rhodium(III) complexes equipped with a suitable atropchiral cyclopentadienyl ligand, in conjunction with a carboxylic acid additive, enables an enantioselective and high yielding access to such spirocyclic sultams.

Die pharmazeutisch relevante Sulfonamidgruppe erweist sich als kompetente dirigierende Gruppe für [Cp*Rh(OAc)2]‐katalysierte C‐H‐Funktionalisierungen. Umsetzungen der cyclometallierten Zwischenstufe mit internen Alkinen bieten Zugang zu einer breiten Auswahl von Sultamderivaten. Die Reaktionen ergeben hohe Ausbeuten und verlaufen am besten unter aeroben Bedingungen mit katalytischen Mengen CuOAc als Oxidationsvermittler. Cp*=C5Me5.